Synthetic degradable polymer scaffolds have been proposed as a new means of tissue reconstruction and repair. The scaffold serves as both physical support and adhesive substrate for isolated cells during in vitro culturing and subsequent in vivo implantation. Scaffolds are utilized to deliver cells to desired sites in the body, to define a potential space for engineered tissue, and to guide the process of tissue development. Cell transplantation on scaffolds has been explored for the regeneration of skin, nerve, liver, pancreas, cartilage and bone tissue using various biological and synthetic materials.
In an alternate approach, degradable polymeric scaffolds are implanted directly into a patient without prior culturing of cells in vitro. In this case, the initially cell-free scaffold needs to be designed in such a way that cells from the surrounding living tissue can attach to the scaffold and migrate into it, forming functional tissue within the interior of the scaffold.
A variety of synthetic biodegradable polymers can be utilized to fabricate tissue engineering scaffolds. Poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and their copolymers are the most commonly used synthetic polymers in tissue engineering. However, in principle, any biodegradable polymer that produces non-toxic degradation products can be used. The potential utility of a polymer as a tissue engineering substrate is primarily dependent upon whether it can be readily fabricated into a three-dimensional scaffold. Therefore, the development of processing techniques to prepare porous scaffolds with highly interconnected pore networks has become an important area of research.
Solvent casting is one of the most widely used processes for fabricating scaffolds of degradable polymers (see Mikos et al., Polymer, 35, 1068-77, (1994); de Groot et al., Colloid Polym. Sci., 268, 1073-81 (1991); Laurencin et al., J Biomed. Mater. Res., 30, 133-8 (1996)). U.S. Pat. No. 5,514,378 discloses the basic procedure in which a polymer solution is poured over a bed of salt crystals. The salt crystals are subsequently dissolved away by water in a leaching process. De Groot et al. disclose a modified leaching technique in which the addition of a co-solvent induces a phase separation of the system upon cooling through liquid-liquid demixing. While this separation mechanism leads to the formation of round pores embedded within the polymer matrix, most of the pores are of insufficient size to form a highly interconnected network between the larger pores formed by leaching.
The existing processing methods produce poor scaffolds with a low interconnectivity, especially when a basic leaching method, such as the method disclosed in U.S. Pat. No. 5,514,378, is used. Particles, when dispersed in a polymer solution, are totally covered by the solution, limiting the interconnectivity of the pores within the scaffolds.
U.S. Pat. No. 5,686,091 discloses a method in which biodegradable porous polymer scaffolds are prepared by molding a solvent solution of the polymer under conditions permitting spinodal decomposition, followed by quenching of the polymer solution in the mold and sublimation of the solvent from the solution. A uniform pore distribution is disclosed. A biomodal pore distribution would increase the degree of pore interconnectivity by creating additional channels between the pores, thereby increasing total porosity and surface area.
U.S. Pat. No. 5,723,508 discloses a method in which biodegradable porous polymer scaffolds are prepared by forming an emulsion of the polymer, a first solvent in which the polymer is soluble, and a second polymer that is immiscible with the first solvent, and then freeze-drying the emulsion under conditions that do not break the emulsion or throw the polymer out of solution. This process, however, also produces a more uniform pore size distribution, with the majority of the pores ranging from 9 to 35 microns in diameter.
There remains a need for biodegradable porous polymer scaffolds for tissue engineering having a bimodal pore size distribution providing a highly interconnected pore network, as well as methods by which such scaffolds may be made. Based on a more advanced scientific rationale, polymeric scaffolds with a bimodal pore size distribution may have significant advantages. Pores in the size range of 50 to 500 micron diameter provide sufficiently open space for the formation of functional tissue within the scaffold while the presence of a large number of smaller pores forming channels between the larger pores would increase cell-cell contact, diffusion of nutrients and oxygen to the cells, removal of metabolic waste away from the cells, and surface patterning to guide the cells. This new design concept for degradable polymeric scaffolds requires the presence of a bimodal pore size distribution with larger pores of 50 to 500 micron diameter and smaller pores creating channels between the larger pores.